The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be a high risk for the eventual development of the visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressure. These so called normotension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
It has been found that serotonergic compounds which possess agonist activity at 5-HT2 receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888. Compounds that act as agonists at 5-HT2 receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 discloses certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT2c agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 discloses tryptamine derivatives that are 5-HT2 agonists for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 discloses a method for treating malaria using 5-HT2A/2C agonists. U.S. Pat. No. 5,902,815 discloses the use of 5-HT2A agonists to prevent adverse effects of NMDA receptor hypo-function. WO98/31354A2 discloses 5-HT2B agonists for the treatment of depression and other CNS conditions. Agonist response at the 5-HT2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT2c receptor possible [Psychopharmacology, Vol. 121:357, 1995].
The present invention is directed to substituted 3-(2-aminoethyl)-1H-indazol-5-ols, some of which are novel. It is believed that these compounds will have a high affinity for and function as agonists at the serotonergic 5-HT2 receptor, and will thereby be useful for lowering and controlling normal or elevated intraocular pressure (IOP) and treating glaucoma. When a phenolic moiety is included in this substitution, e.g. a hydroxyl group at indazole ring position five, such compounds can be particularly sensitive to oxidation reactions well known to occur with phenolic compounds in general, including the related hydroxytryptamines [J. Phys. Chem. 103, 8606 (1999), Chem. Res. Toxicol. 11, 639 (1998), J. Org. Chem. 52, 2817 (1987), J. Pharm. Sci. 77, 911 (1988)], which are of particular relevance to the present application. Protection of such hydroxy substituted phenols from oxidation can be accomplished by derivatization of the aryl hydroxy group to provide a suitable ester, carbamate, or carbonate. Though the ester, carbamate, or carbonate derivatives do not themselves possess a high affinity for the above mentioned receptors, they do have utility in the treatment of glaucoma since suitably protected phenols can be cleaved in vivo either by chemical hydrolysis or through the action of tissue esterases. Such cleavage would deliver the desired therapeutic agent, that is, the desired novel 5-hydroxy-indazole compounds of the present invention. The concept of utilizing such derivatized phenolic compounds as chemical delivery agents is well known in the art [Drugs Pharm. Sci. 53, 221 (1992), Pharm. Res., 168 (1984)].
The chemical synthesis of 3-(2-dimethylamino-ethyl)-1H-indazol-5-ol has been reported with no comment on the utility of the compound [J. Amer. Chem. Soc. 79, 5245–5247 (1957); J. Amer. Chem. Soc. 80, 965 (1958)].
The chemical synthesis of 1-(2-aminopropyl)-1H-indazol-6-ol and other ring substitution variants has been reported in published International Patent Application No. WO98/30548 (1998). The utility cited for the compounds of this application is for treating central nervous system diseases such as sexual disorders, genital insufficiency, appetite regulation disorders, anxiety, depression, and sleep disorders. There is no contemplation of ophthalmic use noted in this application. Published International Patent Application No. WO00/12482 (2000) discloses certain 1-(indazol-3-yl)-2-propylamine derivatives that are 5-HT2 agonists for the treatment of disorders of the central nervous system.